Crystal structure of the carbapenemase OXA-24 reveals insights into the mechanism of carbapenem hydrolysis

Journal of Biological Chemistry

Amini

et al. 2011

Background: OXA-58 is a carbapenem-hydrolyzing class D ␤-lactamase (CHDL) found in Acinetobacter baumannii. Results: OXA-58 exploits a carbamylated lysine in its catalysis. The deacylating water molecule comes from the ␣-face. Conclusion: CHDLs employ the same hydrolytic machinery as oxacillinases. Structural changes in the active site may lead to imipenem hydrolysis. Significance: This study provides insights for the design of CHDL inactivators.

Section: Structural Investigation Of the Interactions Between ␤-Lactasupporting

confidence: 59%

Section: Mechanism Of ␤-Lactammentioning

confidence: 82%

Section: Mechanism Of ␤-Lactammentioning

confidence: 97%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Hydrolytic Mechanism of OXA-58 Enzyme, a Carbapenem-hydrolyzing Class D β-Lactamase from Acinetobacter baumannii

Verma

Journal of Biological Chemistry

Amini

et al. 2011

β‐Lactam Antibiotics

Burger's Medicinal Chemistry and Drug Discovery

Fisher

Mobashery

2010

The β‐lactam classes of antibacterials are preeminent in the treatment of bacterial infection due to their unparalleled clinical efficacy and clinical safety. Following the discovery of the penicillins, successive β‐lactam drug discovery has added the cephalosporin, penem cephamycin, clavulanate, monobactam, nocardicin, and carbapenem subclasses. The driving force behind much of this era of discovery is the staggering ability of pathogenic bacteria to adapt previous generations of the β‐lactam by the acquisition and expression of resistance mechanisms. Although many factors contribute to β‐lactam resistance, alterations to the molecular targets of the β‐lactams (the penicillin binding proteins) and the use of enzymes (the β‐lactamases) capable of the hydrolytic deactivation of the β‐lactams are paramount. This review traces the historical development of β‐lactam drug discovery, with emphasis on the most recent progress in the medicinal chemistry, biochemistry, and microbiology of the β‐lactams leading to the discovery of new generation β‐lactam antibacterials effective against the Gram‐negative and ‐positive bacterial pathogens of current medical concern.

Medicinal Chemistry of β‐Lactam Antibiotics

Burger's Medicinal Chemistry and Drug Discovery

Llarrull

Fisher

et al. 2021

The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.